Yenlin Huang

Quantitative and qualitative investigation into the impact of focused ultrasound with microbubbles on the triggered release of nanoparticles from vasculature in mouse tumors.

Ultrasound-mediated microbubble destruction may enhance the release of nanoparticles from vasculature to tumor tissues. In this study, we used four different sizes of lipid-coated CdSe quantum dot (LQD) nanoparticles ranging from 30 to 180 nm, 1.0-MHz pulsed focused ultrasound (FUS) with a peak acoustic pressure of 1.2-MPa, and an ultrasound contrast agent (UCA; SonoVue) at a dose of 30 microL/kg to investigate any enhancement of targeted delivery. Tumor-bearing male Balb/c mice were first injected with UCA intravenously, were then sonicated at the tumors with FUS, and were finally injected with 50 microL of the LQD solution after the sonication. The mice were sacrificed about 24h after the sonication, and then we quantitatively and qualitatively evaluated the deposition of LQDs in the tumors by using graphite furnace atomic absorption spectrometry (GF-AAS), photoluminescence spectrometry (PL), and harmonic generation microscopy (HGM). Further, immunoblotting analysis served to identify the biochemical markers reflecting the vascular rupture. The experimental results show that the amount of LQDs deposited in tumor tissues was greater in cases of FUS/UCA application, especially for smaller LQDs, being 4.47, 2.27, 0.99, and 0.82 (microg Cd)/(g tumor) for 30, 80, 130, and 180 nm of LQDs, respectively; compared to 1.12, 0.75, 0.26, and 0.34 (microg Cd)/(g tumor) in absence of FUS/UCA. The immunoblotting analysis further indicates that FUS-induced UCA oscillation/destruction results in rupture areas in blood vessels increasing the vascular permeability and thus justifying for the higher quantity of nanoparticles deposited in tumors.

EFFECTS OF FOCUSED ULTRASOUND AND MICROBUBBLES ON THE VASCULAR PERMEABILITY OF NANOPARTICLES DELIVERED INTO MOUSE TUMORS

Ultrasound sonication with microbubbles (MBs) was evaluated for enhancement of the release of nanoparticles from vasculature to tumor tissues. In this study, tumor-bearing Balb/c mice were insonicated with focused ultrasound (FUS) in the tumors after the injection of MBs (SonoVue) and then lipid-coated quantum dot (LQD) nanoparticles (130 +/- 25 nm) were injected through the tail vein. We studied the effects of the injected MB dose (0-300 microL/kg), sonication duration (0-300 s) and treatment-procedure sequence on the accumulation of nanoparticles in the tumors 24 h after the treatment and the time response of the accumulation (0.5-24 h). After the treatment, the mice were sacrificed and perfused and then the tumor tissues were harvested for quantifying the amount of nanoparticles using graphite furnace atomic absorption spectrometry (GF-AAS). The results showed that pulsed-FUS sonication with MBs can effectively enhance the vascular permeability for LQD nanoparticle delivery into the sonicated tumors. It indicates that this technique is promising for a better nanodrug delivery for tumor chemotherapy.

Fasting Glucose Levels in Predicting 1-Year All-Cause Mortality in Patients Who Do Not Have Diabetes and Are on Maintenance Hemodialysis

Chronic inflammation and malnutrition relate to increased risks for cardiovascular death. This study compared fasting glucose levels (FGL) and impaired fasting glucose (IFG) with malnutrition and inflammation in nondiabetic maintenance hemodialysis (MHD) patients to investigate the adverse affects and risks for mortality. In total, 693 MHD patients were enrolled in this study and followed up for 1 yr. Geographic, hematologic, biochemical, and dialysis-related data were collected. According to 1997 and 2003 definitions, all patients were classified into three groups: Diabetic, nondiabetic with IFG, and nondiabetic with normal FGL. More diabetic and nondiabetic with IFG group patients were malnourished (chi(2) = 24.55, P < 0.0001) and had inflammatory changes (chi(2) = 9.32, P = 0.0095) than those with normal FGL. The IFG group had higher high-sensitivity C-reactive protein and ferritin and lower serum albumin, creatinine levels, and normalized protein catabolic rate than the normal FGL group. Age and parameters of nutrition and inflammation were associated with FGL. Stepwise multiple regression analysis demonstrated that FGL were negatively associated with serum albumin (P = 0.0026) and positively correlated with Log high-sensitivity C-reactive protein (P = 0.0004) in nondiabetic MHD patients. In addition, after 1 yr of follow-up, Cox multivariate analysis demonstrated that, after adjustment for other significant related factors, FGL (relative risk 1.049; 95% confidence interval 1.007 to 1.093; P = 0.0232) or presence of IFG (relative risk 3.798; 95% confidence interval 1.168 to 12.344; P = 0.0265) was a significant risk factor for 1-yr all-cause mortality of these patients. On the basis of these findings, basal FGL or presence of IFG, a preventive and treatable status, plays an important role in inflammation, malnutrition, and short-term mortality of nondiabetic MHD patients.

Association of environmental cadmium exposure with inflammation and malnutrition in maintenance haemodialysis patients

BACKGROUND Chronic inflammation and malnutrition are associated with increased risk of cardiovascular death, and may cause protein-energy wasting in individuals with chronic kidney disease. Raised blood cadmium (Cd) levels were observed in maintenance haemodialysis (HD) patients in previous studies. However, the correlation of Cd exposure with inflammation and malnutrition remains uncertain. This study examined the possible adverse effects of environmental Cd exposure in maintenance HD patients. METHODS A total of 954 maintenance HD patients were enrolled and divided into four equal-sized groups based on blood Cd levels. Geographic, haematological, biochemical and dialysis-related data were obtained. The analysis included values for nutritional and inflammatory markers. RESULTS Abnormal blood Cd levels (> or =1 microg/L) were exhibited in 26.8% (256/954) of studied subjects. More subjects in the highest quartile group were malnourished (chi- square = 23.27; P < 0.0001) and had inflammatory changes (chi-square = 13.99; P = 0.0029) than in the lowest quartile group. Stepwise multiple regression analysis revealed a significant inverse correlation between serum albumin and blood Cd levels. Notably, a 10-fold increase in blood Cd levels was associated with a 0.06 g/dL decrease in serum albumin levels (P = 0.0060). Multivariate regression analysis also demonstrated a positive correlation between inflammatory risk (high-sensitivity C-reactive protein >3 mg/L) and blood Cd levels. The risk ratio of inflammation with a 10-fold increase in blood Cd levels was 1.388 (95% CI: 1.025-1.825, P = 0.0336). CONCLUSIONS Environmental Cd exposure is significantly associated with malnutrition, inflammation and even protein-energy wasting in maintenance HD patients. It is important for this population to avoid diets with high Cd concentrations and smoking.

High‐calcium dialysate: A factor associated with inflammation, malnutrition and mortality in non‐diabetic maintenance haemodialysis patients

Aim:  Chronic inflammation, which is common in dialysis patients, often causes malnutrition and even protein‐energy wasting. However, the association of high‐calcium dialysate with malnutrition and/or inflammation in non‐diabetic maintenance haemodialysis patients remains unclear. This study investigated the possible adverse effects of high‐calcium dialysate and mortality in this population.

Evaluation of Lymphatic and Vascular Invasion in Relation to Clinicopathological Factors and Treatment Outcome in Oral Cavity Squamous Cell Carcinoma

AbstractThis study evaluated the associations between lymphatic and vascular invasion of oral cavity squamous cell carcinoma (OSCC) and clinicopathological manifestations, as well as their impact on patient outcomes after treatment.In total, 571 patients with primary OSCC who underwent surgery with or without adjuvant therapy were enrolled.Lymphatic and vascular invasion were found in 28 (5%) and 16 (3%) patients, respectively. Significant associations were found between lymphatic and vascular invasion and overall stage (P < 0.001 and P = 0.020, respectively), tumor stage (P = 0.009 and P = 0.025, respectively), nodal metastasis (both P < 0.001), extracapsular spread (both P < 0.001), perineural invasion (both P < 0.001), bone invasion (P = 0.004 and P = 0.001, respectively), depth of invasion (P < 0.001 and P = 0.001, respectively), and pathologic differentiation (P = 0.002 and P < 0.001, respectively). In the analysis of adverse events during follow-up, neither lymphatic nor vascular invasion was statistically associated with local recurrence, neck recurrence, and distant metastasis. Although lymphatic invasion exhibited significant associations with poorer overall survival (P < 0.001), disease-specific survival (P < 0.001), and disease-free survival (P = 0.01), it was not demonstrated to be an independent prognostic factor in all multivariate analyses.Although both lymphatic and vascular invasion are associated with many clinicopathological manifestations, neither affects the occurrence of locoregional recurrence and distant metastasis in patients with OSCC after treatment.

Cadmium excretion predicting hospital mortality and illness severity of critically ill medical patients

Objective:To determine the prognostic value of day 1 urine excretion of cadmium (1st DUE-Cd) for predicting outcomes in intensive care unit (ICU) patients. Design:Prospective study. Setting:ICUs in Chang Gung Memorial Hospital, Lin-Kou Medical Center, Taiwan, ROC. Patients:Two hundred one ICU patients. Interventions:Urine and blood samples were taken within 24 hours after admission. Measurements and Main Results:Disease severity, hospital mortality, and number of organ failures were evaluated in each medical ICU patient. Stepwise multiple linear regression analysis indicated that a history of chronic hepatitis, serum albumin, and glutamic-pyruvic transaminase were significantly related to 1st DUE-Cd after adjusting for other related variables. Cox multivariate analysis revealed that serum blood urea nitrogen level and ICU 1st DUE-Cd were significantly related to hospital mortality after other risk factors and scoring systems were adjusted. Each 1-&mgr;g increase in ICU 1st DUE-Cd was associated with a 7% increase in hospital mortality rate. All patients with poisoning magnitude of cadmium excretion (>10 &mgr;g/day) died, except one and those with normal cadmium excretion survived. Chi-square values of the Hosmer-Lemeshow goodness-of-fit test were 6.936 (p = 0.544), and area under the receiver operating characteristic curve was 0.868 (95% confidence intervals: 0.82–0.92) for ICU 1st DUE-Cd. Conclusions:The ICU 1st DUE-Cd may predict hospital mortality in critically ill medical patients. Because of excess mortality and relatively small sample size, the predictive role of DUE-Cd needs further external validation.

Prognostic Stratification of Patients With Advanced Oral Cavity Squamous Cell Carcinoma

Purpose of ReviewPrognosis of advanced oral squamous cell carcinoma remains a challenge for clinicians despite progress in its diagnosis and treatment over the past decades. In this review, we assessed clinicopathological factors and potential biomarkers along with their prognostic relevance in an attempt to develop optimal treatment strategies for these patients.Recent FindingsIn addition to several pathologic factors that have been proposed to improve prognostic stratification and treatment planning in the eighth edition of the American Joint Committee staging manual on cancer, we reviewed some other imaging and clinicopathological parameters demonstrated to be closely associated with patient prognosis, along with the biomarkers related to novel target or immune therapy.SummaryEvaluation of current literature regarding the prognostic stratification used in contemporary clinicopathological studies and progress in the development of targeted or immune therapy may help these patients benefit from tailored and personalized treatment and obtain better oncological results.

Application of a patient-derived xenograft model in cytolytic viral activation therapy for nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) is an Epstein Barr virus (EBV)-related malignancy in which the tumor microenvironment plays a pivotal role in tumor progression. Here, we developed two patient-derived xenograft (PDX) mouse lines from engrafted NPC metastatic tumors. Positive staining for EBV-encoded small RNAs confirmed that these tumors harbored EBV, and gene expression profile analyses further showed that the PDX was highly similar to the primary parent tumor. In vivo drug screening using the PDX system demonstrated that gemcitabine had the best antitumor effect among the tested drugs. The donor of this PDX also showed excellent responsiveness to gemcitabine treatment. The combination of gemcitabine and valproic acid exerted synergistic antitumor effects. Further addition of ganciclovir to this two-drug combination regimen enhanced cytolytic viral activation, yielding the best antitumor response among tested regimens. Treatment with this three-drug combination regimen decreased plasma EBV-DNA load, tumor viral concentration, and the number of viable tumor cells to a greater extent than the two-drug gemcitabine and valproic acid combination. These results highlight the value of PDX models in the development of EBV-targeted strategies to treat NPC.

High expression FUT1 and B3GALT5 is an independent predictor of postoperative recurrence and survival in hepatocellular carcinoma

Cancer may arise from dedifferentiation of mature cells or maturation-arrested stem cells. Previously we reported that definitive endoderm from which liver was derived, expressed Globo H, SSEA-3 and SSEA-4. In this study, we examined the expression of their biosynthetic enzymes, FUT1, FUT2, B3GALT5 and ST3GAL2, in 135 hepatocellular carcinoma (HCC) tissues by qRT-PCR. High expression of either FUT1 or B3GALT5 was significantly associated with advanced stages and poor outcome. Kaplan Meier survival analysis showed significantly shorter relapse-free survival (RFS) for those with high expression of either FUT1 or B3GALT5 (P = 0.024 and 0.001, respectively) and shorter overall survival (OS) for those with high expression of B3GALT5 (P = 0.017). Combination of FUT1 and B3GALT5 revealed that high expression of both genes had poorer RFS and OS than the others (P < 0.001). Moreover, multivariable Cox regression analysis identified the combination of B3GALT5 and FUT1 as an independent predictor for RFS (HR: 2.370, 95% CI: 1.505–3.731, P < 0.001) and OS (HR: 2.153, 95% CI: 1.188–3.902, P = 0.012) in HCC. In addition, the presence of Globo H, SSEA-3 and SSEA-4 in some HCC tissues and their absence in normal liver was established by immunohistochemistry staining and mass spectrometric analysis.